Open AccessFull in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer
Author(s) -
Sandrine M. Caputo,
Mélanie Léoné,
Francesca Damiola,
Åsa Ehlén,
Aura Carreira,
Pascaline Gaidrat,
Alexandra Martins,
Rita D. Brandão,
Ana Peixoto,
Ana Vega,
Claude Houdayer,
Capucine Delnatte,
Myriam Bronner,
Danièle Muller,
Laurent Castéra,
Marine GuillaudBataille,
Inge Søkilde,
Nancy Uhrhammer,
Sophie Demontety,
Hélène Tubeuf,
G Castelain,
Uffe Birk Jensen,
Ambre Petitalot,
Sophie Krieger,
Cédrick Lefol,
Virginie Moncoutier,
Nadia BoutryKryza,
Henriette Roed Nielsen,
Olga M. Sinilnikova,
Dominique StoppaLyonnet,
Amanda B. Spurdle,
Manuel R. Teixeira,
Florence Coulet,
Mads Thomassen,
Étienne Rouleau
Publication year - 2018
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.24671
Subject(s) - exon , breast cancer , ovarian cancer , biology , genetics , cancer , gene , germline , exon skipping , cancer research , medicine , bioinformatics , oncology , alternative splicing
Germline pathogenic variants in the BRCA2 gene are associated with a cumulative high risk of breast/ovarian cancer. Several BRCA2 variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 BRCA2 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*10 25 . These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in BRCA1 or BRCA2 gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only BRCA2 delta-exon 3 will be associated with an increased risk of breast and ovarian cancer.